Lentiviruses, like HIV-1, could potentially be used as vectors for delivery and stable gene expression in non-dividing cells. We are interested in the use of HIV-I based vectors for the future targeted gene delivery to post-mitotic cells of the nervous system. These vectors could be a very useful tool to study cell function and to treat neurological dysfunction. We have generated pseudotype HIV-1 like particles carrying the vesicular stomatitis virus glycoprotein G or the amphotropic MoMLV envelope protein. These particles all have a broad host range. In contrast to the commonly used Moloney murine leukemia virus, this HIV-1 lentivirus was able to infect a variety of dividing and non-dividing cells including contact inhibited human skin fibroblasts and CD34 cells as well as HeLa cells and U937 cells. We have been able to infect and express a reporter surface protein such as the heat stable antigen (CD24) as demonstrated by FACS analysis of transduced cells. Transduction efficiency was often between 50 and 80%. It was reduced in the presence of azidothymidine, demonstrating that transduction required reverse transcription. In order to target these virus particles to specific cells of the nervous system, we have developed a model system, trying to target cells that express CD4 on the cell surface by a virus that carries CD24. HIV-I-like particles that encoded CD24 replacing the HIV-I Env protein were generated that contained CD24 in the particle envelope. Using an antibody bridge consisting of biotinylated anti-CD24 antibodies together with a streptavidin protein junction, we were able to specifically bind these CD24(+) particles to CD4(+) cells with low background levels. Binding required the presence of all components of this antibody bridge as well as CD4 and CD24 on the cell and particle, respectively. This demonstrates the specific cell binding of virus particles that can be achieved by this procedure. In the future, this should also allow the targeting of specific neuronal cell surface markers. The major task will be to combine this specific cell binding with a membrane fusion function to allow stable transduction of the cells. Specific cell targeting will be very important for the efficacy and safety of lentiviral vectors in a gene therapy approach.